Parkinson's disease is a progressive neurodegenerating disease which usually affects elderly patients, and the number of parkinsonian patients is growing with progressive aging of society. Parkinson's disease pathogenesis is characterized by impairment in coordinated motor function such as rest tremor, rigidity, akinesia, postural instability and the like. It is thought that Parkinson's disease results from deficiency of dopamine in the striatum, which is caused by degeneration of dopamine neuron in the substantia nigra. For that reasons, L-dopa or dopamine D2 receptor agonists are used for the treatment of Parkinson's disease.
L-dopa is a precursor of dopamine, and is metabolized to dopamine which exerts its efficacy in the brain. Since L-dopa has a very short serum half-life, L-dopa is administered usually in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor and/or a catechol-O-methyltransferase inhibitor, which are the metabolizing enzyme inhibitors of L-dopa.
Dopamine D2 receptor agonists exert an anti-Parkinson's effect by directly stimulating dopamine D2 receptors of the striatum. And, it is known that the dopamine D2 receptor agonists are useful for treating restless legs syndrome, hyperprolactinemia or the like (for example, see Non-patent literature 1 or 2).
Various ergot or non-ergot dopamine D2 receptor agonists are known as dopamine D2 receptor agonist (for example, see Patent literatures 1 to 3 about ergot dopamine D2 receptor agonist, and see Patent literatures 4 to 6 about non-ergot dopamine D2 receptor agonist).
The non-ergot dopamine D2 receptor agonists have the disadvantage of a duration of action is shorter than the ergot dopamine D2 receptor agonists, since the serum half-life of them is shorter than the ergot dopamine D2 receptor agonists (for example, see Non-patent literature 3). And more, the non-ergot dopamine D2 receptor agonists have problems of side effects such as sudden onset of sleep, somnolence or the like.
The ergot dopamine D2 agonists show the long-term effectiveness compared to the non-ergot dopamine D2 receptor agonists. However, recently it has been reported that the risk of onset of cardiac valvular disease increases when taken long-term and high dose of pergolide which is a typical ergot dopamine D2 receptor agonist. So, the periodic monitoring of echocardiography and the like are required during administering the ergot dopamine D2 receptor agonists. Since it is reported that cardiac valvular disease is caused by the growth stimulation of the cardiac valvular cells by the stimulation activity of 5-HT2B receptor as pathogenesis of cardiac valvular disease, the relevance of cardiac valvular diseases and the stimulation activity of 5-HT2B receptor is strongly suggested (for example, see Non-patent literature 4).
Accordingly, it has been expected for novel dopamine D2 receptor agonists exhibiting potent and lasting dopamine D2 receptor agonistic activities with less 5-HT2B receptor stimulating activities.
As octahydropyridoquinazoline derivatives, the following compounds are known (see Patent literature 7).
in which RA is CH2OH, CH2OCH3 or CH2SCH3.
However, anything is neither described nor suggested about the compounds substituted with an ureido group as RA in the Patent reference 7. And more, dopamine D2 receptor stimulation activity of the compounds of Patent literature 7 are not insufficient as shown in the following test example.